Dynamin-2 reduction rescues the skeletal myopathy of a SPEG-deficient mouse model

Qifei Li , Jasmine Lin , Jeffrey J. Widrick , Shiyu Luo , Gu Li , Yuanfan Zhang , Jocelyn Laporte (1, 2) , Mark A. Perrella , Xiaoli Liu , Pankaj B. Agrawal

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

Striated preferentially expressed protein kinase (SPEG), a myosin light chain kinase, is mutated in centronuclear myopathy (CNM) and/or dilated cardiomyopathy. No precise therapies are available for this disorder, and gene replacement therapy is not a feasible option due to the large size of SPEG. We evaluated the potential of dynamin-2 (DNM2) reduction as a potential therapeutic strategy because it has been shown to revert muscle phenotypes in mouse models of CNM caused by MTM1, DNM2, and BIN1 mutations. We determined that SPEG-β interacted with DNM2, and SPEG deficiency caused an increase in DNM2 levels. The DNM2 reduction strategy in Speg-KO mice was associated with an increase in life span, body weight, and motor performance. Additionally, it normalized the distribution of triadic proteins, triad ultrastructure, and triad number and restored phosphatidylinositol-3-phosphate levels in SPEG-deficient skeletal muscles. Although DNM2 reduction rescued the myopathy phenotype, it did not improve cardiac dysfunction, indicating a differential tissue-specific function. Combining DNM2 reduction with other strategies may be needed to target both the cardiac and skeletal defects associated with SPEG deficiency. DNM2 reduction should be explored as a therapeutic strategy against other genetic myopathies (and dystrophies) associated with a high level of DNM2.

Domaines: Biochimie, Biologie Moléculaire

Qifei Li, Jasmine Lin, Jeffrey J. Widrick, Shiyu Luo, Gu Li, et al.. Dynamin-2 reduction rescues the skeletal myopathy of a SPEG-deficient mouse model. JCI Insight, 2022, 7 (15), ⟨10.1172/jci.insight.157336⟩. ⟨hal-04219143⟩